The overall objective of this project is to provide information useful in predicting conditions in which non-target vertebrates may be unusually susceptible (or resistant) to the toxic action of pesticides, or of other chemicals including drugs, as a result of exposure to pesticides. The proposed research will focus on the anticholinesterase insecticides. It will examine the dynamic relationships among their sites of: 1) biotransformation, 2) primary action and 3) secondary action that are critical in determining their toxicity and that may be subject to modulation by other chemicals. It is expected that these toxicological studies will provide information useful in assessing the health hazards of pesticides, singly and in combinations, and will also further characterize the basic biological processes affected by these compounds. Specific hypothesis or questions to be addressed include: 1. What is the correlation between development of tolerance and changes in muscarinic receptor binding and function? 2. Is there any memory impairment following subchronic exposure to organophosphate insecticides? 3. Is there an altered sensitivity to anticholinergic and antidepressants in organophosphate-tolerant animals? 4. Can muscarinic receptors in circulating lymphocytes be used as peripheral markers of nerve tissue receptor response to exogenous chemicals? 5. What is the comparative metabolism of phosphorothionate insecticides in vivo and in vitro, in isolated hepatocytes and cell-free systems? 6. Does subchronic exposure to the carbamate propoxur alter hepatic metabolism of propoxur itself and/or of other insecticides?